Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.
Solid human tumors are often infiltrated by host immune cells, which can have a diverse effect on tumor progression. Among other cell types, macrophages are known to be a major component in the leukocyte infiltrate in tumors. These tumor-associated macrophages, (TAMs), have a complex dual function in their interactions with neoplastic cells (Mantovani, et al., Trends Immunol. 23: 549-555, 2002). First, TAMs stimulate cell destruction through antigen presentation to T-cells, which induces cytotoxic T-cells to kill tumor cells bearing the presented antigen. In contrast, TAMs also promote cell proliferation and angiogenesis, thus affecting tissue growth.
These contradictory effects can be explained in terms of the “macrophage balance hypothesis,” which asserts that the outcome of the interaction between macrophages and neoplastic cells depends on the number of macrophages recruited to the tumor microenvironment and their state of activation (Mantovani, et al., Immunol. Today 13: 265-270, 1992; Bingle, et al., J. Pathol. 196: 254-265, 2002; Nesbit, et al., J. Immunol. 166: 6483-6490). Nesbit, et al. have shown that, in a mouse model, high levels of monocyte chemoattractant protein-1 (MCP-1) secreted by melanoma cells is associated with massive monocyte/macrophage infiltration into the tumor mass, leading to destruction of the tumor within a few days. However, low levels of secreted MCP-1 stimulated angiogenesis and tumor growth. Furthermore, ex vivo-grown cytotoxic macrophages that recognize and destroy tumor cells, but not normal cells, are effective in murine models of metastasizing tumors. (Andreesen, et al., J. Leukocyte Biol. 64: 419-426, 1998). Accordingly, immunomodulation, in particular regulating macrophage activity, has potential as a therapeutic strategy for the treatment of tumors, secondary metastasis, and other disorders.
Angiocidin is a protein, originally isolated from lung carcinoma, that is overexpressed in many tumor systems (Zhou et al., J. Cell. Biochem. 92: 125-146, 2004; Poon, et al., Clin. Cancer Res. 12: 4150-4157, 2004). Angiocidin is a receptor for thrombospondin-1 and is a potent inhibitor of angiogenesis and tumor cell proliferation (U.S. 2003/0180295; Zhou et al., J. Cell. Biochem. 92: 125-146, 2004). These functions of angiocidin are mediated by α2β1 integrin (Sabherwal, et al., Exp. Cell Res. 312: 443-453, 2006). In addition, angiocidin has important immunomodulatory effects on monocytes that can affect the course of disease.